Therapy-related leukemia: clinical characteristics and analysis of new molecular risk factors in 96 adult patients.

Therapy-related leukemia or myelodysplasia (t-leuk/MDS) is a serious problem that is increasing in frequency. We studied the clinical characteristics of 96 patients (pts) with a mean age of 48 years, and analyzed the molecular parameters that could predispose to t-leuk/MDS. Hematological malignancies were the most common primary (53%), followed by breast and ovarian cancer (30% combined). The mean latency until the development of t-AML was 45.5 months. Median survival was 10 months. Cytogenetics was abnormal in 89% of pts. FLT3 internal tandem duplications were found in six of 41 (14.6%) pts, of whom four had an abnormal karyotype. Analysis of drug metabolism and disposition genes showed a protective effect of the CYP3A4 1*B genotype against the development of t-leuk/MDS, whereas the CC genotype of MDR1 C3435T and the NAD(P)H:quinone oxidoreductase1 codon 187 polymorphism were both noncontributory. Microsatellite instability (MSI) analysis using fluoresceinated PCR with ABI sequence analyzer demonstrated that 41% of pts had high levels of MSI in four or more of 10 microsatellite loci. Immunohistochemistry demonstrated reduced expression of MSH2 and MLH1 in 6/10 pts with MSI as compared to 0/5 of pts without MSI. In conclusion, genetic predisposition as well as epigenetic events contribute to the etiology of t-AML/MDS.

Efficient transduction of human hematopoietic cells with the human multidrug resistance gene 1 via SV40 pseudovirions.

Transduction of MDR1 may be of use in chemoprotection of normal bone marrow (BM) cells during treatment of malignancies, or as a selectable marker for the transfer of other genes into the BM, a critical target for the cure of many diseases. To that aim, the human multidrug resistance gene MDR1 was cloned into an SV40 pseudoviral vector containing the SV40 origin of replication (ori) and encapsidation signal (ses), and the plasmid was encapsidated in COS cells as SV40/MDR1 pseudovirions. Expression of the human MDR1 gene was demonstrated in murine MEL cells infected with SV40/MDR1 pseudovirions, using a monoclonal antibody (MPK16) specific for the human 170-kD P-glycoprotein. Functional P-glycoprotein was demonstrated by resistance to colchicine in NIH-3T3 cells infected with SV40/MDR1 pseudovirions. Activity of P-glycoprotein was assayed by rhodamine-123 dye exclusion and fluorescence-activated cell sorter analysis (FACS) in various cell types including hematopoietic cells. Highly efficient gene transfer and expression was demonstrated in all murine and human cell types tested, including primary human BM cells. Using multiplicities of infection (moi) of 1-2, over 95% of cells were found to become MDR1+. The percent of MDR1+ cells was proportional to the moi. We conclude that the SV40 pseudoviral vector is efficient for gene transmission into human hematopoietic cells.

Thalassemia major 1995: older patients, new therapies.

There have been many advances in supportive treatment used for beta-thalassemia major. Survival has increased substantially, and an increasing number of patients reach adolescence and adulthood. These older patients present new clinical challenges. Complications of transfusion, most commonly hepatitis C, are still a cause of mortality and morbidity. The achievement of optimal growth and development, including fertility, is an important goal of conservative management. Long-term survival has also been achieved with bone marrow transplantation. Assessment of growth, development and iron balance in the years after transplantation reveals residual problems requiring treatment despite cure of thalassemia. New therapies of beta-thalassemia are still being developed, both supportive and curative in nature. Supportive care improvements include oral chelation and methods to increase HbF production. Advances in curative modalities include use of new sources of stem cells, such as cord blood and fetal liver. In the future, gene therapy may allow for cure of the older patient without the mortality and morbidity of allogenic transplantation. Treatment of thalassemia major requires consideration of the available therapeutic options for each patient, and the risk/benefit ratio of a supportive versus curative approach.

Pathophysiology of alpha- and beta-thalassemia: therapeutic implications.

At the molecular level, the underlying cause of thalassemia is any of a number of genetic lesions that reduce or abolish the production of the globin chains of hemoglobin. The resulting chain imbalance is the key factor initiating the damage to the red blood cell (RBC) and it is the major pathophysiological event in all forms of the thalassemia syndromes. In this review we will outline some of the cellular and systemic processes that have been implicated in the development of the disease. When relevant, we will discuss the ways in which these processes can be altered in a therapeutic manner.

Decreased digoxin cardioinactive-reduced metabolites after administration as an encapsulated liquid concentrate.

The generation by intestinal bacteria of large amounts of cardioinactive metabolites of digoxin with a reduced lactone ring (digoxin reduction products, or DRP) may be associated with increased dosage requirements. Since DRP excretion varies inversely with bioavailability, we compared the 6-day urinary excretion (CUE) of digoxin and DRP after 0.4-mg doses of an encapsulated liquid concentrate and a standard tablet in 22 normal subjects known to form substantial amounts of DRP. Mean (+/- SE) CUE of digoxin was greater with the capsules than the tablets (195.9 +/- 8.6 and 137.5 +/- 6.3 micrograms). CUE of DRP was less after the capsules (60.8 +/- 5.5 and 102.7 +/- 9.5 micrograms). Percent DRP was greater after the tablets in every subject (mean for tablets, 41.2 +/- 2.7%; capsules, 23.5 +/- 1.8%). Patterns of DRP excretion differed with the two preparations, probably reflecting differences in the routes whereby digoxin reached the colon. The use of highly bioavailable capsules in subjects with heavy DRP production should minimize metabolic inactivation during digoxin therapy.

New trends in the treatment of beta-thalassemia.

Thalassemia is the world's most common hereditary disease, and is a paradigm of monogenic genetic diseases. Because of increased population mobility, the disease is found today throughout the world, even in places far from the tropical areas in which it arose. Therapy of thalassemia has in the past been confined to transfusion and chelation. Recently, novel modes of therapy have been developed for thalassemia, based on the pathophysiology and molecular pathology of the disease, both of which have been extensively studied. This review will discuss the therapeutic modalities currently in use for the supportive treatment of thalassemia, both those that are standard therapy and those that are in clinical trials. We will include transfusion, chelation (intravenous and oral), antioxidants and various inducers of fetal hemoglobin (hydroxyurea, erythropoietin, butyrates, hemin). Most of the newer therapies are suitable primarily for thalassemia intermedia patients. In addition, the treatment modalities currently in use for the curative treatment of thalassemia major will be discussed, including bone marrow transplantation in its various forms. Experimental therapeutic methods, such as intrauterine bone marrow transplantation and gene therapy, are included. Physicians caring for thalassemia patients have an increasing variety of treatment options available. Future clinical studies will determine the place of newer agents and modalities in improving the quality of life as well as the life expectancy of thalassemia patients.

Urinary excretion of reduced metabolites of digoxin.

The urinary excretion of the relatively cardioinactive reduced metabolites of digoxin, dihydrodigoxin and related compounds was measured by radioimmunoassay in 131 normal subjects during studies of the bioavailability of digoxin preparations. Digoxin reduction products (DRP) constitute more than 5 percent of the excretion of digoxin and its metabolites in one-third of the volunteers after the administration of single or multiple doses of digoxin. There was little or no output of DRP during the first 8 hours after a single dose, with maximal excretion usually occurring on the second day. Most subjects who excreted more than 5 percent DRP on one occasion did so with each subsequent exposure to digoxin. Six volunteers, however, in whom substantial amounts of DRP had previously been found, failed to excrete detectable quantities after subsequent doses. In two, this change occurred shortly after they took erythromycin. Urinary DRP were less after the intravenous administration compared to the oral administration of digoxin. After oral doses, DRP excretion tended to vary inversely with the bioavailability of the preparation. The findings are consistent with the hypothesis that DRP are formed as the result of the activity of a variable component of the intestinal flora. Prospective studies will be necessary to prove this hypothesis.

Psychiatric illness in a general urban emergency room: daytime versus nighttime population.

Two hundred adults presenting to the emergency room of an urban general hospital were interviewed by a standardized technique to evaluate the existence of a current or previous psychiatric illness. Half of the subjects presented between 8:00 a.m. and 4:00 p.m. (daytime group), and 100 presented between 12:00 a.m. and 8:00 a.m. (nighttime group). In the nighttime population 65% were judged to have current or past psychiatric illnesses. In the daytime population only 36% had current or past psychiatric illnesses. The differences between the 2 populations was highly significant. Fewer than 10% of the 200 patients presented with neuropsychiatric symptoms in their chief complaints.

Severe migratory polyarthritis following in vivo CAMPATH-1G.

CAMPATH-1G is an IgG2b rat antihuman (CDw52) monoclonal antibody (MoAb) which is currently being used for T cell depletion in the setting of allogeneic bone marrow transplantation (BMT). In addition it elicits substantial lymphoid depletion, an effect which is being explored for remission induction in patients with lymphoid malignancies and for treating patients with various autoimmune disorders, in particular rheumatoid arthritis. Recently, in vivo CAMPATH-1G has been introduced to achieve increased immunosuppression in the pretransplant conditioning, for prevention of graft rejection following T cell depleted BMT. Here we describe a patient with T cell lymphoblastic lymphoma who received in vivo CAMPATH-1G as part of the pretransplant conditioning regimen and who, 6 days after the first dose, developed severe migratory polyarthritis. This is the first report of severe migratory polyarthritis as a very unusual complication following CAMPATH-1G MoAb administration.

6;9 translocation in myelodysplastic syndrome.

The 6;9 chromosomal translocation [t(6;9)] is usually associated with acute nonlymphocytic leukemia, and carries a poor prognosis. We present a case of refractory anemia with excess of blasts (RAEB) accompanied by t(6;9). Review of the literature revealed an additional ten patients in which myelodysplastic syndrome (MDS) was associated with the chromosomal translocation 6;9. The patients tend to be younger then the average MDS patient and, unlike leukemia, in which this translocation is associated with a poor prognosis, these patients tend to have the same overall RAEB and refractory anemia with excess of blasts in transformation (RAEBt) prognosis. It is therefore possible that this chromosomal aberration should not be considered as an unfavorable prognostic factor in MDS.

De novo acute myeloid leukemia with near-pentaploidy: diploid karyotype and lymphoblastic phenotype at relapse.

Hyperploidy is a rare finding in leukemias, with isolated cases of tetraploidy reported in acute myeloblastic and acute lymphblastic leukemias. We report the first case of acute myeloid leukemia with near-pentaploidy (5 n+/-) which was present in 100% of metaphases at diagnosis. By light microscopy, the leukemic blasts were exceptionally large and coarsely granulated. Following one cycle of induction chemotherapy, complete morphologic and cytogenetic remission was documented. Four weeks later relapse occured, at which time the karyotype was diploid and the morphological and immunophenotypic characteristics were those of a lymphoid leukemia. However, the presence of three aberrant chromosomes (5q+, 6q+ and 20q+) confirmed that this was clonal evolution of the original myeloid leukemia. To the best of our knowledge, this case represents the first report of near-pentaloidy in de novo, pretreatment human leukemia.

Reported alcohol consumption and the serum carbohydrate-deficient transferrin test in third-year medical students.

The serum carbohydrate-deficient transferrin (CDT) test was performed on 143 third-year medical students along with questionnaires for the self-reporting of alcohol consumption during the last 2 weeks, the last 6 months, and questions on any alcohol-related untoward events. We found that the CDT test has poor sensitivity for detecting binge drinking in our population of students, despite some likely under-reporting of drinking. Self-reporting of drinking is commonly unreliable, and we found no significant correlation between the CDT concentrations in serum and the magnitude of self-reported alcohol use during 2-week and 6-month periods. Hangover was by far the commonest self-reported untoward event, and there was a highly significant relationship (P < 0.001) between drinking and untoward events. From a small population of non-drinkers, we estimated the reference ranges for CDT to be <27 U/l for men and <35 U/l for women.

Faculty development in emergency medicine.

Faculty development is an important, multifaceted topic in academic medicine. In this article, academic emergency physicians discuss aspects of faculty development, including: 1) a department chair's method for developing individual faculty members, 2) the traditional university approach to promotion and tenure, 3) faculty development in a new department, and 4) personal development.

Candida abscess of the thyroid in a patient with acute lymphocytic leukemia.

A case of Candida abscess of the thyroid in a patient with acute lymphoblastic leukemia is described. The patient developed this rare complication after treatment with steroids and combination chemotherapy, during therapy with broad spectrum antibiotics for febrile neutropenia. Prior to the thyroiditis the patient had pulmonary aspergillosis. The abscess developed during treatment with high dose Amphotericin B. Unlike previous cases, the Candida was isolated to the thyroid, with no evidence of Candidemia or Candida infection in other sites.

A mutation in the promoter of the multidrug resistance gene (MDR1) in human hematological malignancies may contribute to the pathogenesis of resistant disease.

The overexpression of the multidrug resistance gene MDR1 has been found to be associated with therapy-resistance in hematological malignancies. Yet the cellular mechanisms underlying this increased expression are completely unknown. Point mutations in the MDR1 promoter have been found in osteogenic sarcoma (Stein et al., Eur J of Cancer, 30A: 1541-1545, 1994). We therefore analyzed DNA from hematological malignancies for MDR1 promoter point mutations. Two pairs of overlapping PCR primers were designed which did not amplify the MDR3 gene. Amplified DNA was screened using single strand conformation polymorphism (SSCP). 139 patients and 93 normal controls were studied. Fifteen patients (11%) were found to have abnormal bands on the SSCP analysis. Of these, 9 had acute myeloid leukemia (AML), 4 chronic lymphocytic leukemia (CLL), 1 acute lymphocytic leukemia (ALL), and 1 nonHodgkin's lymphoma (NHL). Sequence analysis revealed that all patients were heterozygous for a point mutation in the promoter (T-C transition at +8). Four normals (4%) were found to be heterozygous for the mutation. Confirmation of the mutation was performed by oligonucleotide probe hybridization. All but two of the AML patients have died due to chemoresistant disease (one is lost to followup). Of the CLL patients, one is alive with progressive disease, and the others have died. Further studies will assess the effect of this mutation on MDR1 gene transcription.

Orthopaedic trauma in men: the relative risk among drinkers and the prevalence of problem drinking in male orthopaedic admissions.

Admissions to an acute male orthopaedic ward (n = 369) were asked about their accident, their alcohol consumption, and alcohol-related problems in the past 2 years. Comparing their consumption with that of males from a community survey revealed an increased risk of orthopaedic admission in drinkers consuming 21 units of alcohol/week or over, relative to drinkers consuming less than 21 units/week, in the age group 31-50 years. In all, 34% of the sample met a criterion for problem drinking based on self-reported alcohol consumption and/or medical and social problems associated with alcohol. In 13%, alcohol was viewed by the patient as having contributed to the accident, and in 19% according to the interviewer's perception of whom 76% were classifiable as problem drinkers. Twenty-six men said the accident had made them think about changing their drinking habits. Detection of problem drinking in orthopaedic male admissions is possible and could be usefully linked to a counselling service.

Opening the Airway: Equipment and Techniques.

When an airway is blocked, immediate action is necessary. Knowing what equipment to use and having it available can mean the difference between life and death.

Airway Obstruction: The Heimlich Maneuver.

Choking results in many deaths each year. Yet a simple procedure that can be performed by almost anyone, even the victims, could prevent this from happening.

Cardiac Arrest.

In brief: Immediate cardiopulmonary resuscitation (CPR) is required to provide a victim of cardiac arrest with artificial ventilation and circulation. The author reviews the basic principles of CPR (establishing an airway, providing ventilation, and initiating cardiac massage) and discusses the underlying dysrhythmias associated with cardiac arrest. Depending on the dysrhythmia involved, appropriate treatment may include electrical therapy (defibrillation) and/or pharmacologic therapy (eg, intravenous epinephrine, lidocaine, bretylium, and sodium bicarbonate).

Emergency Evaluation of Chest Pain.

In brief: Occasionally the team physician may be called on to examine someone, a spectator for example, who has chest pain. After ensuring that the person's vital signs are stable, the physician must determine whether the cause is potentially catastrophic or relatively minor. The author describes the distinguishing factors.